Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH3:14]>O1CCOCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:14])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cc(S(N)(=O)=O)ccc1F
Reaction time: 0.5 h

Procedure:
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) in 1,4-dioxane (10 mL) at 0° C. was treated dropwise with a 7 M ammonia solution in methanol (3.57 mL) and stirred for 30 minutes. A small amount of solid was removed by filtration and discarded. The filtrate was concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and triturated with diethyl ether to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmoles) in dichloromethane (25 ml) and pyridine (5.0 ml) under argon was cooled to 0° C. and was treated dropwise with ethyl chloroformate (1.2 ml of 0.7%, 12.0 mmoles). After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 1 hour. It was then diluted with ethyl acetate and the resulting solution was washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester as a light yellow foam (3.71 g). This material was used in the next reaction without purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([O:18][CH3:19])[CH:6]=[CH:5][C:4]1=2)#[N:2].Cl.[CH2:21](N)[CH2:22][NH2:23].N>CO.CO.C(Cl)(Cl)Cl>[NH:2]1[CH2:21][CH2:22][N:23]=[C:1]1[CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([O:18][CH3:19])[CH:6]=[CH:5][C:4]1=2
Reactant: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C#N
Reactant: NCCN
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C1=NCCN1
Temperature: 0 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
N-(5-Cyano-2-methoxy-5,6,7,8-tetrahydronaphthalen-1-yl)methane-sulfonamide (1.5 g, 5.4 mmol) was dissolved in 200 ml of MeOH and cooled to 0° C. The solution was then treated with dry HCl gas for 2 h, sealed tightly and stored for 12 h at 25° C. The solvent was removed and the residue was redissolved in 100 ml of MeOH, followed by addition of ethylenediamine (0.67 ml, 10 mmol). The resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (25% NH3 sat'd MeOH-CHCl3) to provide 1.3 g (76%) of the desired product. 1H NMR (300 MHz, CD3OD): δ 1.78 (m, 2H), 1.96 (m, 1H), 2.12 (m, 1H), 2.95 (broad t, 2H), 2.98 (s, 3H), 3.82 (s, 3H), 3.90 (broad s, 4H), 4.11 (t, 1H, J=6.3 Hz), 6.96 (t, 1H, J=8.9 Hz), 7.05 (t, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[O:22]=[C:23](Cl)[O:24][C:25](Cl)(Cl)Cl.CO>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[N:10]([C:9]=2[C:23]([O:24][CH3:25])=[O:22])[CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n1CCC2
Reaction time: 8 h

Procedure:
6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated with 1 drop of triethylamine (about 50 mg). A solution of diphosgene (0.5 g, 2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solution at RT and it is stirred for 8 h. Methanol (abs., 3 ml) is then added, and the mixture is stirred at RT for a further 12 h. The solvent is completely removed in vacuo (45° C.). The resinous residue is dissolved in CHCl3 (20 ml) and washed twice with water (20 ml). After the removal of the solvent in vacuo, a residue which is recrystallized from a little diisopropyl ether is obtained from the CHCl3 phase dried using Na2SO4 sicc.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].CN1CCN(C)C1=O.P(Cl)(Cl)([Cl:26])=O.[CH3:29][N:30]([CH3:32])[NH2:31]>O>[Cl:26][C:9]1[N:8]=[C:7]([NH:31][N:30]([CH3:32])[CH3:29])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CN(C)N
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CN(C)Nc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h

Procedure:
To 300 mg (1.45 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 1 ml of 1,3-dimethyl-2-imidazolidinone and 1.23 g (8.05 mmol) of phosphorus oxychloride, and the resulting mixture was subjected to heating under reflux for 3 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 3 ml of acetonitrile, followed by addition of 520 mg (8.69 mmol) of N,N-dimethylhydrazine and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off to give 2-chloro-4-(2,2-dimethylhydrazino)-6-nitroquinazoline. After 2.00 ml (26.65 mmol) of allylamine was added thereto and then the mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 73 mg (17.5%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (5 g, 27.7 mmol) and chlorotert-butyldimethylsilane (5 g, 33.3 mmol) in DMF was treated with triethylamine (4.6 ml). The mixture was stirred at room temperature for 20 hours. More chlorotert-butyldimethylsilane (0.8 g) and triethylamine (0.8 ml) were added, the resulting mixture was stirred at room temperature for another 2 hours, poured into saturated aqueous sodium bicarbonate (500 ml). The mixture was stirred at room temperature for 5 minutes and extracted with ether. The organic phase was washed with brine, dried over sodiun sulfate and concentrated in vacuo. Bulb-to-bulb distillation gave the title material (7.39 g, 91%) as a colorless oil (b.p. 104-105° C./0.025 mm Hg).
Reaction SMILES: Cl.[CH3:2]O.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:2])=[O:16])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
15 ml of 10% hydrogen chloride-methanol was added to 1.07 g (5.0 mmol) of 4-(4-hydroxyphenyl)benzoic acid and the mixture was refluxed under heating for 5 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto and the solution was extracted twice with a chloroform-methanol mixed solution (10:1 (v/v)). The extract was washed with a sodium hydrogencarbonate aqueous solution and dried (MgSO4). The solvent was distilled off to obtain 0.97 g (4.25 mmol) of methyl 4-(4-hydroxyphenyl)benzoate as a faint yellow powder. Its spectroscopic data are as follows:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.54 g, 1.24 mmol) prepared in Example 14c, triethylsilane (1.98 mL, 12.4 mmol), trifluoroacetic acid (0.96 mL, 12.4 mmol) and dichloromethane (20 mL), to yield the title compound (0.54 g, 99%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:15]>>[F:23][C:18]1[CH:17]=[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2cc(-c3cc(F)cc(F)c3)oc2c1
Yield: 60 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 60% following procedures A.2 and A.5; m.p. 208-209° C.; IR 3353, 3092, 1615, 1780, 1432, 1349, 1125 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 10.05 (s, 1H), 9.54 (s, 1H), 7.49 (d, J=6.8 Hz, 2H), 7.47 (s, 1H), 7.15 (t, J=8.6 Hz, 1H), 6.43 (s, 1H), 6.21 (s, 1H); 13C-NMR (126 MHz, δ ppm, CDCl3) 165.1 (dd, J=246.3 Hz, 13.3 Hz), 158.9, 158.9, 152.9, 151.65, 135.7 (t, J=10.6 Hz), 112.7, 107.7 (dd, J=21.0 Hz, 6.8 Hz), 103.3 (t, J=26.1 Hz), 102.6, 99.2, 90.8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[N:11]=[C:10]3[N:14]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH:9]3[O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)=[CH:28][CH:27]=1)=[O:42]
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(NC(=O)C(C)(C)C)cc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 16A) (100 mg, 0.258 mmole) in CH2Cl2 (2 mL) is added NEt3 (72 μL, 0.515 mmole) and pivaloylchloride (48 μL, 0.387 mmole). The reaction mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure. AcOEt is added to the residue and the organic phase is washed with water and dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (100:0) to (90:10) to afford 2,2-dimethyl-N-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-propionamide melting at 120° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:59][C:60]([CH3:62])=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:60]([CH3:62])[CH3:59])[C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((S)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (43.8 mg, 0.075 mmol) and sodium triacetoxyborohydride (80.1 mg, 0.377 mmol) in DMF (1 mL) was added acetic acid (22.7 mg, 21.6 μL, 0.377 mmol) and acetone (17.6 mg, 22.2 μL, 0.302 mmol). The reaction mixture was heated at 60° C. for 6.5 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H1): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
Sodium triacetoxyborohydride (32.0 g, 151.0 mmol) is added to a stirred solution of tert-butyl 4-oxo-1-piperidine carboxylate (20.0 g, 100.4 mmol), isobutylamine (10.5 ml, 105.7 mmol), acetic acid (6.0 ml, 104.8 mmol) and 1,2-dichloroethane (300 ml). The reaction is stirred for 18 hours at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (24.5 g, 95%) of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=257.1 (M+1); 1H NMR (CDCl3): δ=4.01 (2H, br s), 2.78-2.75 (2H, m), 2.60-2.53 (1H, m), 2.42 (2H, d), 1.83-1.64 (3H, m), 1.56 (1H, br s), 1.44 (9H, s), 1.28-1.18 (2H, m), 0.90 (6H, d).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C=O.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.[C:24](=O)(O)[O-].[Na+]>O1CCOCC1.C(O)(=O)C>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:24][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[CH:18][NH:19]2
Reactant: Fc1cccc2[nH]ccc12
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(Cc2c[nH]c3cccc(F)c23)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred solution of 1.8 grams (0.011 mole) of ethyl piperidin-4-ylcarboxylate in 10 mL of dioxane was cooled to 0° C., and 10 mL of acetic acid, followed by 0.9 mL of aqueous 37% formaldehyde were added. To this was then slowly added a solution of 1.5 grams (0.011 mole) of 4-fluoroindole in 10 mL of dioxane. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about five hours. After this time the reaction mixture was again cooled to 0° C., and neutralized with an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride, dried with sodium sulfate, and filtered. The filtrate was then passed through a pad of silica gel. The eluate was concentrated under reduced pressure, yielding 1.2 grams of ethyl N-(4-fluoroindol-3-ylmethyl)piperidin-4-ylcarboxylate, mp 96°-105° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Sc1nc(CCO)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.9 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.4 g) obtained in Example 4 was dissolved in dichloromethane (50 mL), trifluoroacetic acid (50 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (100 mL). Thionyl chloride (8 mL) was added under ice-cooling, and the mixture was refluxed for 4 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (6.7 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]2[NH:9][C:10]([NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl.C(OCC)(=O)C>CO>[C:23]1([CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]3[NH:9][C:8]4[CH:29]=[CH:30][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[CH2:19][CH2:18]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2[nH]c(NCC3CCN(CCCc4ccccc4)CC3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc2[nH]c(NCC3CCN(CCCc4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After suspending 2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid methyl ester (3.2 mmol) in methanol (10 ml), a 4N lithium hydroxide aqueous solution (5.4 ml, 21.4 mmol) was added. The reaction mixture was stirred at 50° C. for 2 hours and then cooled to room temperature. Next, 1N hydrochloric acid was added dropwise to adjust the pH to approximately 6.0. Ethyl acetate (1 ml) was added to the aqueous solution and the mixture was stirred for 3 hours, and then the precipitate was filtered out to obtain 2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid. The compound was identified by LC-MS.
Reaction SMILES: COC(O[CH:6]([CH3:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>C(Cl)Cl.[Pd].CCCCCCC>[C:15]1(=[O:25])[N:19]([CH:6]([CH3:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: CCOC(=O)/C=C/C(C)OC(=O)OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C(C)N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
Reaction of 1 (rac-Ethyl (2E)-4-(methoxycarbonyloxy)pent-2-enoate) (104 mg, 0.50 mmol) with phthalimide (147 mg, 1.0 mmol), Cs2CO3 (40.7 mg, 0.125 mmol) and 5 mol % [Pd] in CH2Cl2 (10 ml) at room temperature according to Example 2. Flash chromatography (AcOEt:heptane fraction 25:75) yields 16 (rac-Ethyl (2E)-4-phthalimidopent-2-enoate) (124 mg, 90%) as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:11][C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1)=[O:13].IC.[C:30](=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:11][C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:20])[N:18]([CH3:30])[CH:19]=1)=[O:13]
Reactant: COc1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2C)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)c(F)c1

Procedure:
In analogy to example 161, step 1, 5-[3-(2-fluoro-4-methoxy-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=380.3 [M+H]+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22](=[O:24])(=[O:23])[CH3:21])(=[O:24])(=[O:23])[CH3:21]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Temperature: 5 °C
Yield: 89.5 %

Procedure:
A 5,000 mL, 3-necked flask equipped with a mechanical stirrer, thermometer and 500 mL addition funnel was charged with tetraethylene glycol (388 g, 2.0 mol) dichloromethane (1,500 mL) and triethylamine (445 g, 4.40 mol). The mixture was stirred and cooled to ca. 5° C., and methanesulfonyl chloride (470 g, 4.1 mol) was added dropwise over 3 hours. The reaction mixture was stirred an additional 3 hours while warming to 25° C., then water (1,000 mL) was added and the phases were separated. The organic layer was washed with ice-cold 6 N HCl (2×1,000 mL) and then washed with 5% Na2CO3, saturated aqueous NaCl, dried, filtered and evaporated in vacuo to yield 627 g (90%) of tetraethylene glycol dimesylate, i.e.,