Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]=1[O:34][CH2:35]C1C=CC=CC=1)=[O:7])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)([CH2:47][CH3:48])CC>C1COCC1>[CH2:27]([O:26][C:10]1[C:9]([O:34][CH2:35][C:48]2[CH:47]=[CH:10][CH:9]=[CH:8][CH:6]=2)=[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:11]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)NNC(C)=O)n1-c1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nnc(C)o2)n1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(2-acetylhydrazinecarbonyl)-1H-pyrrole-2-carboxylate (31) (155 mg, 0.56 mmol) and Burgess reagent (132 mg, 0.56 mmol) were dissolved in THF (2 mL). The mixture was heated in a microwave at 100° C. for 30 min and the volatiles removed in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-30% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrole-2-carboxylate (UL1-087) (115 mg, 77%) as a colourless oil: m/z 540 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.46 (m, 2H), 7.43-7.31 (m, 8H), 7.18-7.12 (m, 2H), 6.93-6.87 (m, 2H), 5.17 (s, 2H), 5.07 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.35 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[C:14]([N+:33]([O-:35])=[O:34])=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[CH2:38]([O:40][C:41]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)=[O:42])[CH3:39].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[C:14]([N+:33]([O-:35])=[O:34])[C:13]([C:47]4[CH:48]=[C:43]([CH:44]=[CH:45][CH:46]=4)[C:41]([O:40][CH2:38][CH3:39])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])c1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
Cesium carbonate (1.69 g, 5.19 mmol) was added to Pd(Ph3P)4 (250 mg, 0.216 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (2.00 g, 4.33 mmol), 3-(ethoxycarbonyl)phenylboronic acid (1.01 g, 5.19 mmol). Dioxane (36 mL) and water (7 mL) was added at rt and the mixture was degassed 3×. The reaction was heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, Tilt and concentrated. The crude solid was triturated with DCM to give the titled compound (1.70 g, 85%). 1H NMR (400 MHz, DMSO-d6) δδ ppm 8.55-8.61 (1H, m), 8.54 (1H, s), 8.00-8.09 (3H, m), 7.95 (1H, s), 7.73 (1H, s), 7.61-7.70 (2H, m), 7.45 (2H, t, J=8.91 Hz), 4.35 (2H, q, J=7.19 Hz), 2.83 (3H, d, J=4.52 Hz), 1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.62 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([OH:11])=O.S(Cl)([Cl:14])=O.CN(C=O)C>ClCCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sc(Cl)c(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1sc(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 20.4 g (0.088 mole) of 3,4,5-trichloro-2-thiophenecarboxylic acid, 7.3 mL (0.1 mole) of thionyl chloride, 0.2 mL of DMF and 80 mL of 1,2-dichloroethane was heated at reflux temperature for 3 h. The reaction mixture became a clear solution after 1 h of heating. The mixture was allowed to cool to RT, concentrated in vacuo and exposed to high vacuum to give 22.0 g (>98% wt) an oil which solidified upon standing to an off-white powder, mp 37°-41° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13]1(=O)[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1>Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:10][C:5]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C1CCCCO1
Agent: Cl
Product: OCCCCc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 77.3 %

Procedure:
4-Trifluoromethyl-1,2-phenylenediamine (3 g, 17.03 mmol) and delta-valerolactone (1.78 ml, 18.74 mmol) in 4M HCl (15 ml) were heated to 110° C. for 18 h. The reaction mixture was quenched by addition to sat. NaHCO3(aq) (100 ml), and the mixture was extracted with EtOAc (3×100 ml). The combined organics were dried (MgSO4) and concentrated to afford a brown oil which was triturated with Et2O to afford 3.4 g (77.3%) of 4-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-butan-1-ol as a tan powder. MS (ESI+) for C12H13F3N2O m/z 258.95 [M+H]+; HPLC ret. time, 1.22 min. 1H NMR (500 MHz, MeOD) δ ppm 7.82 (1H, br. s.), 7.66 (1H, br. s.), 7.44-7.55 (1H, m), 3.62 (2H, t, J=6.46 Hz), 2.99 (2H, t, J=7.65 Hz), 1.89-2.00 (2H, m), 1.58-1.68 (2H, m).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 10 g (26.3 mmol) of N-[[4-(phenylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester from Example 6a in 50 mL of anhydrous dimethylformamide, was added 9.80 g (52.7 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, followed by 10.9 g (79.0 mmol) of powdered potassium carbonate. The mixture was heated to 50° C. with vigorous stirring and maintained there for 20 hours. A sample was removed and analyzed by HPLC and shown to contain starting material, whereupon 4.90 g (26.3 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, followed by 3.63 g (26.3 mmol) of powdered potassium carbonate was added and heating continued for an additional 4 hours at 70° C. The solution was cooled, ethyl acetate and water added, the organic layer separated and washed 4 times with brine, dried with sodium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 0-5% methanol/ethyl acetate to yield 12.9 g of pure N-[[4-(phenylthio)phenyl]sulfonyl]-N-[2-(4-morpholinyl)ethyl]glycine, 1,1-dimethylethyl ester, m/e=490 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C@:29]12([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:36]([CH3:38])([CH3:37])[CH:33]([CH2:34][CH2:35]1)[CH2:32][C:30]2=[O:31]>CO>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH3:37][C:36]1([CH3:38])[C@:29]2([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:30]([CH2:32][C@H:33]1[CH2:34][CH2:35]2)=[O:31]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
12.25 g (0.03 mol) of amlodipine (Hanmi Pharm. Co. Ltd.) was dissolved in 50 ml of methanol, cooled to 10° C., and a solution of 7.8 g (0.336 mol) of (1S)-(+)-10-camphor sulfonic acid (Aldrich) in 19.5 ml of methanol was gradually added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the solid formed compound was filtered, washed with 25 ml of methanol, and dried to obtain 16.7 g (yield: 86.8%) of the title compound in the form of a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:9])=[O:8].[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1I.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)(C)C.O1CCOCC1>[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=1[O:2][CH3:1])[C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:9])=[O:8])=[CH:11]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Reactant: Clc1ccc(I)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4Br)cccc3c2)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A pressure vessel was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (5.00 g, 8.81 mmol), 2-bromo-4-chloro-1-iodobenzene (5.59 g, 17.6 mmol) and Pd(dppf) Cl2 DCM (1.44 g, 1.76 mmol). Dioxane (44.1 mL) and t-butanol (44.1 mL) were added to the reaction vial followed by 1.9 M sodium carbonate in water (13.9 mL, 26.4 mmol). The reaction vial was then swept with nitrogen and sealed with a screw cap. The reaction mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated to 50° C. After 2 h, LC/MS indicated about 90% conversion of boronic ester to the desired product as [M+Na]+=652. The mixture was cooled to room temperature and filtered through a fritted funnel with EtOAc (150 mL). The filtrate was washed with brine. The organic layers were combined, dried with MgSO4, filtered and concentrated to afford a black oil. The mixture was purified by MPLC (300 g silica gel column eluting with 0 to 50% EtOAc:Heptane) to afford a white solid. MS (ESI): 651.8 [M+Na]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.66 (s, 3H), 5.18 (d, J=16 Hz, 1H), 5.24 (d, J=16 Hz, 1H), 6.31-6.41 (m, 2H), 6.95-7.04 (d, J=9 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.64 (d, J=6.1 Hz, 2H), 7.78-7.80 (m, 2H), 7.98 (d, J=2.25 Hz, 1H), 8.30 (d, J=9.4 Hz, 1H), 8.38 (s, 1H), 8.65 (m, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:43]=[CH:42][C:17]3[NH:18][C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([CH:33]6[CH2:35][CH2:34]6)=[O:32])[CH:28]=5)[N:23](C5CCCCO5)[N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:43]=[CH:42][C:17]3[NH:18][C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([CH:33]6[CH2:34][CH2:35]6)=[O:32])[CH:28]=5)[NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:13]1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(N5CCOCC5)ccc4[nH]3)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
TFA (0.238 mL, 3.08 mmol) was added to solution of N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (15 mg, 0.031 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.59 (d, 1H, J=1.2 Hz), 7.66 (m, 2H), 7.47 (dd, 1H, J=1.6 and 9.2 Hz), 7.31 (dd, 1H, J=2.0 and 9.2 Hz), 7.16 (s, 1H), 3.87 (m, 4H), 3.23 (m, 4H), 1.85 (m, 1H), 1.03 (m, 2H), 0.93 (m, 2H); ESI-MS [M+H]+: 403.19.
Reaction SMILES: C(C1C=CC(N[N:10]=[C:11]2[C:16]3=[N:17][C:18]4[C:23]([C:24](=[O:25])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)=CC=1)#N.[OH-].[NH4+:27]>O>[C:24]([C:23]1[CH:22]=[C:21]2[C:12]3[CH2:13][CH2:14][N:15]4[C:24](=[O:25])[C:23]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[N:17]=[C:16]4[C:11]=3[NH:10][C:20]2=[CH:19][CH:18]=1)#[N:27]
Reactant: N#Cc1ccc(NN=C2CCCn3c2nc2ccccc2c3=O)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CCn1c-3nc2ccccc2c1=O
Yield: 92 %

Procedure:
1 g of 6-[(4-Cyano-phenyl)-hydrazono]-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline-11-one is heated in 10 g of polyphosphoric acid at 180° C. for 30 minutes. After cooling the reaction mixture is diluted with 40 ml of water and the pH is adjusted to 5 by adding 25 V/W% ammoniumhydroxide solution. The precipitated product is filtered, washed with water and dried. 0.88 g (92%) of 10-cyano-7,8-dihydro-5H,13H-indolo[2',3';3,4]pyrido[2,1-b]quinazoline-5-one are obtained which after recrystallization from dimethylformamide melts at 255° C.
Reaction SMILES: [Si:1](=[O:3])=[O:2].[OH2:4].[NH3:5].[OH2:6]>>[Si:1]([O-:6])([O-:4])([O-:3])[O-:2].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5]
Reactant: N
Reactant: O
Reactant: O=[Si]=O
Product: [NH4+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Silicon dioxide commercially obtained in the form of fine powder or gelatine can not successfully polymerize the black liquor when the silicon dioxide diluted with water is added to the liquor and heated and dehydrated to react. However, if silicon dioxide and the black liquor is heated to a high temperature in an autoclave to form the silicate, the condensation polymerization can be accomplished. Further, the condensation polymerization is also carried out successfully with the combined use of gelatinous silicon dioxide and ammonia water. It is presumed in the process of heating and dehydration that ammonium silicate is first formed and then it is decomposed into silicic acid.
Reaction SMILES: C([O:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13])(=O)C1C=CC=CC=1.[OH-].[K+].CO.O.OC(CCCC)CC#C>C(OCC)(=O)C>[OH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13]
Reactant: C#CC[C@H](CCCC)OC(=O)c1ccccc1
Agent: C#CCC(O)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#CC[C@@H](O)CCCC
Reaction time: 24 h

Procedure:
A solution of 1.15 g. (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 899) and 1.40 g. (25 mmoles) of potassium hydroxide in 50 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]D25 = +17 ± 1.0°(C=0.77, ethyl acetate). This compound has the (S)-configuration.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22]CC)=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:8]([CH3:19])=[C:7]([C:20]([OH:22])=[O:21])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A 15.91 g portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixture of 200 ml of ethanol and 20 ml of tetrahydrofuran at 80° C., and 96.01 ml of a 5 M sodium hydroxide aqueous solution was added thereto, followed by overnight stirring at the same temperature and then further stirring at 100° C. for 6 hours. The reaction liquid was concentrated to about 150 ml, and, under ice-cooling, 6 M hydrochloric acid was added thereto until pH became 1. The resulting solid was collected by filtration and washed with water to obtain 14.04 g of 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid as a light brown solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][OH:37])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:38][C:39]1[CH:40]=[N:41][C:42](Cl)=[N:43][CH:44]=1>C1COCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][O:37][C:42]3[N:43]=[CH:44][C:39]([Br:38])=[CH:40][N:41]=3)[N:20]=[CH:19][N:18]=2)(=[O:14])=[O:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCC#CCO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCC#CCOc1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 29 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 150 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 10) was added. After stirring for 0.5 h, 64 mg of 5-bromo-2-chloropyrimidine was added. Stirring was continued for 40 h at 40° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crystallised from 2-propanol to give 126 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: tR=6.07 min, [M+1]+=656.24, [M−1]+=654.34.
Reaction SMILES: N1C=CC(C2SC=C(C([N:14]=[N+:15]=[N-:16])=O)N=2)=CC=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](C2SC=C(C(O)=O)N=2)[CH:18]=1.[OH-].[Na+:32].C(Cl)(=O)C(Cl)=O>O>[N-:14]=[N+:15]=[N-:16].[Na+:32].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:14]=[N+:15]=[N-:16])[CH:18]=1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: [N-]=[N+]=NC(=O)c1csc(-c2ccncc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [N-]=[N+]=Nc1cccnc1
Product: [N-]=[N+]=[N-]

Procedure:
In a manner similar to that described for the preparation of 2-(4-pyridinyl)-4-thiazolylcarbonylazide, 6.0 g of 2-(3-pyridinyl)-4-thiazolylcarboxylic acid was treated successively with NaOH, oxalyl chloride and a solution of NaN3 in water to give the 3-pyridinylazide as a pale brown solid. MS m/z: 204.5 (M−N2+H)
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Yield: 72.9 %

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 1.3 starting with 3.5 g of magnesium, 25 g of 1-bromo-4-methoxybenzene, 50 ml of THF and a mixture of 8 g of 5-chloro-1H-indol-2,3-dione in 50 ml of THF. 9.3 g of the expected product are obtained after crystallization from hot iso ether; m.p.=202° C.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].C([OH:19])C.[OH-].[Na+]>O>[NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15](=[O:19])[NH2:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCO
Reactant: CCN(CC)Cc1cc(C#N)cc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)cc(Br)c1N

Procedure:
11 gm of 2-amino-3-bromo-5-cyano-N,N-diethyl-benzylamine were refluxed with a mixture of 70 ml of ethanol and 100 ml of 5 N sodium hydroxide. After cooling, the reaction solution was diluted with 100 ml of water and extracted with chloroform. The chloroform extract was dried over sodium sulfate and evaporated, and the residue was recrystallized from isopropanol, yielding 2-amino-3-bromo-5-carbamoyl-N,N-diethyl-benzylamine, m.p. 140°-142° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH3:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13])=[C:2]([NH:21][C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[N:10]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(F)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-2-fluoro-9-isopropyl-9H-purine (215 mg, 1 mmol), 1-methyl-1H-pyrazol-4-amine (116 mg, 1.2 mmol) in nBuOH (5 mL, 0.2 M) and DIPEA (0.7 mL, 4 mmol) was stirred at ambient temperature for 2 days. LCMS showed major title product with M+1=276.2 amu. This crude product was used in the following step with no isolation.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=O)[CH3:2].C([SiH]([CH2:19][CH3:20])CC)C.F[C:22](F)(F)[C:23]([OH:25])=[O:24]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH2:6][CH2:22][C:23]([OH:25])=[O:24])[C:19]=1[CH3:20])[CH3:2]
Reactant: CC[SiH](CC)CC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
5-Acetyl-2-oxindole (2 g) in 15 mL trifluoroacetic acid in an ice bath was slowly treated with 1.8 g triethylsilane and then stirred at room temperature for 5 hours. One mL of riethylsilane was added and the stirring continued overnight. The reaction mixture was poured into ice water and the resulting precipitate collected by vacuum filtration, washed copiously with water and dried under vacuum to give 1.3 g (71% yield) of the title compound as a yellow solid.