Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([Cl:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pt]=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]2[C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:25][C:26]=1[Cl:31]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Yield: 48.9 %

Procedure:
After dissolving 255 mg of the 4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl amine synthesized in Production Example 153-5 in 10 ml of ethanol and 3 ml of tetrahydrofuran, 100 mg of platinum oxide was added and the mixture was stirred overnight at room temperature under normal pressure in a hydrogen atmosphere. After filtering with celite, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 105 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1cncnc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (483 mg, 3.4 mmol) was dissolved in absolute ethanol (70 mL), and triethylamine (1.4 mL, 10.2 mmol) and 5-(bromomethyl)pyrimidine (882 mg, 5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered. The filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-5-ylmethyl)sulfanyl]pyrimidin-4-ol (12 mg, 2% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.34 (s, 2H), 6.02 (bs, 1H), 8.88 (s, 2H), 9.05 (s, 1H); LRMS (ES+) m/z 235 (100%, M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)[C:25]2([C:35]3=CC4OCOC=4[CH:42]=[C:34]3[O:33][CH2:32]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:42][C@H:34]1[CH2:35][CH2:25][CH2:32][O:33]1)[C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (28%) as a colorless solid: mp 169-170° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.35-7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.56 (d, J=28.1 Hz, 1H), 6.41 (d, J=2.9 Hz, 1H), 4.78-4.67 (m, 2H), 4.52-4.46 (m, 2H), 4.30-3.93 (m, 3H), 3.82-3.93 (m, 2H), 2.99-2.91 (m, 2H), 2.06-1.58 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.7, 156.8, 156.7, 154.3, 142.9, 142.7, 136.1, 136.0, 132.8, 131.5, 131.3, 128.7 (2C), 123.3 (2C), 122.7, 121.9, 121.8, 109.7, 109.6, 109.5, 104.5, 104.4, 92.4, 79.5, 75.6, 75.4, 67.1, 67.0, 57.2, 43.8, 43.7, 28.5, 28.4, 28.1, 25.0, 24.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([N:10]=C=O)([CH3:9])[CH3:8])([CH3:3])=[CH2:2].[N-]=C=O.OC(C)(C)CC(=O)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([NH2:10])([CH3:9])[CH3:8])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: O
Solvent: CC(=O)CC(C)(C)O
Product: C=C(C)c1cccc(C(C)(C)N)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask blanketed with nitrogen was charged with 3-isopropenyl-α,α-dimethylbenzylisocyanate (m-TMI) (475.33 g) and the isocyanate was heated to about 85° C. 4-hydroxy-4-methyl-2-pentanone (274.99 g) was added from an addition funnel to the flask at a fairly rapid rate. The mixture was stirred for two hours and about 0.16 g of dibutyltin dilaurate was added to the mixture, after which the temperature was raised to about 100° C. The reaction mixture was stirred for about 1.5 hours at 100° C. and then allowed to cool and stand at room temperature for approximately 48 hours. Subsequently, about 0.14 g of additional dibutyltin laurate was added and heating at 100° C. was resumed. The reaction mixture temperature was then raised to about 125°-130° C. and the mixture was stirred overnight. Water (800 ml) was added to the cooled reaction mixture and the mixture was distilled. The remaining material in the distillation pot was extracted with toluene. The toluene extract was dried with anhydrous K2CO3, the toluene was distilled and the title product was recovered in a toluene solution.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)[nH]c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 18.3 %

Procedure:
To a solution (80 mL) of ethyl 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (8.6 g) in ethanol was added 10% palladium carbon (50% containing water, 0.86 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 36 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 60 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→5:1) to give the title compound as a brown solid (yield 1.37 g, 18%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[O:31][CH2:30][CH2:29][O:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.Cl>C(O)C>[O:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH:15]([CH3:16])[CH2:14][NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:18][CH2:19]3)[C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CC(CN(C(=O)OC(C)(C)C)c1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Agent: Cl
Solvent: CCO
Product: CC(CNc1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
Compound VII as a crude oil (49.0 g, 0.106 mol) is dissolved in ethanol (150 mL) and to this solution is added 1N HCl solution in ethanol (212 mL). The resulting solution is refluxed for 18 h, then concentrated in vacuum to a small volume (˜100 mL) until product starts to crystallize. Ether (100 mL) is added slowly to resulting slurry, in portions, and the mixture is stirred at ambient temperature for 2 h. Slightly gray crystals are filtered and washed with ethanol/ether (50:50) mixture to afford 22.2 g of compound VIII (49% over 3 steps). The purity is determined to be 97.9% by LC-MS. This batch is then recrystallized from methanol (150 mL) and ether (200 mL) to produce 19.3 g of VIII with 99% purity. 1H NMR (CD3OD) δ 8.01 (m, 2H), 7.30 (d, J=9 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 6.82 (t, J=8.1 Hz, 1H), 6.63 (m, 2H), 4.30 (m, 4H), 4.10 (m, 1H), 3.80–2.90 (m, 9H), 1.55 (d, J=6.2 Hz, 3H). MP=245–248° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])=[CH:16][CH:15]=1.[Cl-].[NH4+]>CCOCC>[ClH:13].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([N:28]([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[OH:27])=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1(O)c1ccc(C(F)(F)F)cc1
Product: Cl
Temperature: 25 °C
Yield: 11.9 %

Procedure:
0.22 g (9.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.03 g (9.0 mmole) of 4-bromo-benzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7.5 mmole) of the 2-[(4-chloro-phenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 58 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.65 g of crude base (85.4% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.50 g of crude base (16.2% of theory) was obtained, from which 0.20 g of 2-[(4-chlorophenyl)dimethylaminomethyl]-(4-trifluoromethylphenyl)cyclohexanol, hydrochloride (6.0% of theory) with a melting point above 240° C. was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])=[N:10][C:11]=2[NH2:17].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CCCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-9H-purin-6-amine and piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:18]([O-])=O.[NH4+:21]>C(N)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:18][NH:21][C:4]2=[O:5]
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: COc1cc(N)c(C(=O)O)cc1OCCCCl
Solvent: NC=O
Product: COc1cc2nc[nH]c(=O)c2cc1OCCCCl
Temperature: 47.5 °C
Yield: 90.2 %

Procedure:
2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (450 gm), formamide (2250 ml) and ammonium formate (200 gm) were heated to 170-180° C. for 3-4 hours. The reaction mass was concentrated under reduced pressure at 140-150° C. The residue was stirred in methanol (1000 ml) at 45-50° C. and cooled to 5-10° C. The solid obtained was filtered to yield the title compound (420 gm, 90% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]=[N+:17]=[N-:18])=[CH:13][C:12]=1[C:21]#[N:22]>C(O)C>[NH2:2][C:1]1[N:16]([CH2:15][C:14]2[CH:19]=[CH:20][C:11]([Cl:10])=[C:12]([C:21]#[N:22])[CH:13]=2)[N:17]=[N:18][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: N#Cc1cc(CN=[N+]=[N-])ccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(Cn2nnc(C(N)=O)c2N)ccc1Cl
Yield: 32.7 %

Procedure:
A stirred suspension of 2-cyanoacetamide (790 mg, 9.40 mmol) in absolute ethanol (40 ml) was treated with sodium methoxide (495 mg, 9.16 mmol) and refluxed 10 minutes. The mixture was cooled slightly, a solution of 4-chloro-3-cyanobenzyl azide (1.35 g, 7.01 mmol) in absolute ethanol (10 ml) was added in one portion, and the mixture was refluxed 2.5 hours. The mixture was filtered hot, the solid was washed with absolute ethanol, and the combined filtrate and wash were evaporated to dryness under vacuum. The residue was triturated with diethyl ether, filtered, and washed twice with diethyl ether. The solid was recrystallized from methanol (6 ml) and dried at 65° C. under vacuum to provide 635 mg (24%) 5-amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 172°-175° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=O.[OH2:21]>C(Cl)(Cl)(Cl)Cl.Cl>[OH:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH:17]([C:9]2[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]([OH:21])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)[C:16]([OH:20])=[O:19])=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C(C(=O)O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 50 °C
Reaction time: 40 h

Procedure:
103 g of 2,6-di-tert.-butyl-phenol (0.5 mol) and 21 g of glyoxylic acid (0.25 mol) of (CHO.COOH) . 1/2 H2O) were dissolved in 300 ml of carbon tetrachloride and stirred at 50° C for about 40 hours. During the first 6 hours, a weak hydrogen chloride stream was passed through the solution, later saturation was completed from time to time by feeding in hydrogen chloride. After condensation was complete, the solvent was eliminated. The product obtained in a pasty form was dissolved and precipitated several times from hexane. The crystallized compound having a faint yellowish tinge melted at 211° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 29 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.56 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.157 g, 0.56 mmol) and 2.0 M aqueous sodium carbonate (0.8 mL, 1.6 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-fluoro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.070 g, 29%) as a solid. MS calcd. for C22H21FNO5S [(M−H)−] 430, obsd. 430.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:12][CH:13]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2cccnc2)nc1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Into a 11 flask, 20 g of 3-pyridine boronic acid, 50 g of 2,5-dibromopyridine, 5.5 g of Pd(PPh3)4, 33.9 g of sodium carbonate, 500 ml of toluene, 150 ml of ethanol, and 150 ml of pure water were put, and the solution was stirred at reflux temperature for 3.5 hours. After heating, the reaction liquid was cooled to room temperature and the organic layer was extracted. The organic layer was concentrated in an evaporator, the concentrates were purified by column chromatography, then, recrystallized in heptane, and thus 27 g of 5-bromo-2,3′-bipyridine was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:24]([O:14][CH:13]([C:15]1[N:16]=[N:17][NH:18][N:19]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CCCCCCc1ccccc1)c1nn[nH]n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nn[nH]n1
Yield: 74.4 %

Procedure:
A solution of 7-phenyl-1-(2H-tetrazol-5-yl)-heptan-1-ol (36 mg, 0.14 mmol), TBSCl (63 mg, 0.42 mmol) and imidazole (28 mg, 0.42 mmol) in DMF (0.7 mL) was stirred at room temperature for 72 h before it was diluted with EtOAc, and washed with H2O and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude material that was purified by flash chromatography (SiO2, 1.5×15 cm, 10% acetone-hexanes) to afford 5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazole (39 mg, 75%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.26 (dd, 2H, J=6.3, 8.4 Hz), 7.16 (m, 3H), 5.25 (t, 1H, J=5.8 Hz), 2.57 (t, 2H, J=7.7 Hz), 1.85 (m, 2H), 1.58 (m, 2H), 1.31 (m, 6H), 0.90 (s, 9H), 0.13 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:13]=[C:14]=O)([CH3:12])[CH3:11])[CH:5]=1)=[CH2:3].[CH:16]1([N:22]=C=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:22]=[C:14]=[N:13][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([CH3:1])=[CH2:3])[CH:5]=2)([CH3:12])[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C=NC1CCCCC1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Product: C=C(C)c1cccc(C(C)(C)N=C=NC2CCCCC2)c1
Temperature: 150 °C

Procedure:
We combined 0.0830 g TPAO, 60.41 g of m-TMI, and 25.04 g cyclohexylisocyanate. After heating at 150° C. for 7 hours, IR showed nearly complete conversion of isocyanates to carbodiimides. 1H-NMR indicated the desired product contaminated with 1,3-dicyclohexylcarbodiimide, and 1,3-bis[2-(3-isopropenylphenyl)-2-propyl]carbodiimide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)OCc2ccccc2)c(S(=O)(=O)Cl)cc1OC
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OCc2ccccc2)c(S(=O)(=O)N2CCOCC2)cc1OC
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 60.1 %

Procedure:
To a stirred mixture of (2-chlorosulfonyl-4,5-dimethoxy-phenyl)-acetic acid benzyl ester (15.0 g, 39.0 mmol) in anhydrous tetrahydrofuran (45 cm3) cooled to 0° C. in an ice bath under an atmosphere of dry nitrogen was added triethylamine (6.00 cm3, 43 mmol). The mixture was stirred 2 minutes and morpholine (3.75 cm3, 43 mmol) was added dropwise to form a solid mass. To efficiently stir the mixture additional anhydrous tetrahydrofuran (145 cm3) was added and the mixture was warmed to ambient temperature over 20 hours. Water was added to the mixture and extracted with ethyl acetate (2×100 cm3). The combined ethyl acetate extracts were dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford a crude tan solid. The crude solid was recrystallized from toluene (150 cm3) to afford the title compound as tan crystals (10.2 g, 60.2%) with a positive ion ESI (M+H)+436.2.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[Cl-:24].C([O:27][C:28](=O)[CH2:29][CH2:30][C:31](O)=O)C>C1C=CC=CC=1>[ClH:24].[CH2:1]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:15][CH2:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC1CCNCC1
Reactant: CCOC(=O)CCC(=O)O
Reactant: [Cl-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCC1CCN(CCCCO)CC1
Product: Cl

Procedure:
To a mixture of 23 grams of 4-n-decylpiperidine and 13 grams of triethylamine in 100 ml. of benzene, is slowly added with agitation 17 grams of succinic acid ethylesterchloride. The reaction is violent and is allowed to go to completion after the addition. The precipitate is filtered off. The solution is added to a mixture of 10 grams LAH in 500 ml. of dry diethylether. The reaction mixture is refluxed for three hours. The reaction complex is decomposed by slow addition of water. The precipitate is filtered off. The ether-benzene solution is dried and evaporated. The residue is distilled to give the desired product at 145°-147° Centigrade/0.01 mm. Hg. The yield is 28 grams (97%). The hydrochloride is precipitated as in Example 1. After recrystallization, the melting point of the hydrochloride is 152°-154° Centigrade.