Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:14])[N:6]([C@H:8]2[CH2:11][C@@H:10]([CH2:12][OH:13])[CH2:9]2)[CH:7]=1.C[N:17]1CCCC1.Cl[Si](C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+](C1C=CC(O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CC#N>[F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:14])[N:6]([C@H:8]2[CH2:11][C@@H:10]([CH2:12][OH:13])[CH2:9]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@@H](CO)C2)cc1F
Reactant: CN1CCCC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1nc(=O)n([C@H]2C[C@@H](CO)C2)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]uracil (139 mg, 0.65 mmol) and methylpyrrolidine (530 mg, 6.2 mmol) in anhydrous CH3CN was treated dropwise with chlorotrimethylsilane (211 mg, 1.9 mmol). The mixture was aged for 1 h at ambient temperature, cooled to 0° C. and treated dropwise over 5 min. with trifluoroacetic anhydride (680 mg, 3.2 mmol). After 40 min. at 0° C. 4-nitrophenol was added to the mixture, and the mixture aged for an additional 2 h at 0° C. The mixture was poured into saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 (3×40 mL). Combined organic phases were dried over magnesium sulfate and then concentrated. The residue was dissolved in dioxane (10 mL) and 30% aqueous NH4OH (2.5 mL) and heated at 50° C. for 40 h in a sealed vessel. The mixture was cooled to ambient temperature and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel with 10% CH3OH in CH2Cl2 with 1% NH4OH (v/v) to give 5-fluoro-1-[cis-3-(hydroxymethyl)-cyclobutyl]cytosine (53 mg, 38%) as a white solid and recovered starting material (50 mg). 1H NMR (DMSO-d6, 400 MHz): δ 1.89 (m, 2H), 2.09 (m, 1H), 2.24 (m, 2H), 3.39 (d, J=5.1 Hz, 2H), 4.56 (broad s, 1H, OH), 4.64 (m, 1H), 7.36 (broad s, 1H, NH2), 7.58 (broad s, 1H, NH2), 7.97 (d, J=7.2 Hz, 1H); MS (FAB): expected for C9H12FN3O2 (M+Li)+220.2. Found 220.19.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)\[CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[OH:25][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:26]=[CH:27][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:8][CH:9]=2)=[CH:14][CH:15]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(=O)CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 4 mL of MeOH to the stirred solvent was added methyl 3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-3-oxopropanoate (0.08 g, 0.178 mmol) and Sodium borohydride (0.008 g, 1.21 mmol) was added 0° C. Then it was stirred at RT for 6 h, after completion of the reaction (reaction monitored by TLC), reaction mass quenched with Ice water and concentrated the reaction mixture and extracted with ethyl acetate. The organic layer washed with brine and dried by anhydrous Na2SO4 and evaporated to dryness, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.04 g, Yield: 50%) 1H NMR (300 MHz, DMSO-d6): δ 7.62-7.65 (m, 2H), 7.32-7.40 (m, 5H), 7.23-7.26 (d, 2H), 6.90-6.93 (m, 4H), 5.36-5.38 (d, 1H) 5.22 (s, 2H), 4.92 (s, 2H), 4.85-4.89 (t, 1H), 4.04 (s, 3), 3.57 (s, 3H), 2.57-2.59 (d, 2H)
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>O>[CH3:11][CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CC1CNCCN1
Solvent: O
Product: CC1CN(c2ccc(C(N)=O)cc2)CCN1
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A mixture of 4-fluorobenzamide (Aldrich; 2.432 g), (RS)-2-methylpiperazine (Aldrich; 4.247 g), and water (9 mL) is heated at 100° C. for 7 days. The mixture is then cooled to 41° C. and water is added. The solid is collected, washed with water and toluene and dried under reduced pressure to give 3.37 g of (RS)-4-(3-methylpiperazin-1-yl)benzamide; 1H NMR (CDCl3, CD3OD) δ1.17, 2.48, 2.82, 2.94-3.15, 3.04, 3.68, 6.89, 7.73.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][CH:6]=[C:7]([CH:8]=[O:9])[C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: CCOC(C(=O)O)c1c(F)ccc(C=O)c1F
Reactant: N#Cc1ccc(CN)cc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C=O)c1F

Procedure:
According to general procedure B (RS)-(2,6-difluoro-3-formyl-phenyl)-ethoxy-acetic acid was reacted with 4-aminomethyl benzonitrile to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-formyl-phenyl)-2-ethoxy-acetamide. Amorphous off-white solid. MS 359.2 ([M+H]+)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:22]2[CH2:24][CH2:23]2)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:22]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)[N:8]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
The solutions of 3.6 g (10.7 mmol) of 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 27D]) in 40 ml of ethanol and of 1.07 g (26.7 mmol) of sodium hydroxide in 5 ml of H2O were mixed and then refluxed for 1 hour. After cooling to ambient temperature, 6.7 ml of 4N aqueous hydrochloric acid was added. The reaction mixture was extracted with three portions of ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous sodium sulfate. The 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid crystallized upon concentrating the solution by evaporation. After cooling in an ice bath, 3.08 g of white crystals were obtained (84% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[O:16][C:17]=2[CH3:18])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(OC)cc3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Yield: 89.4 %

Procedure:
Reaction of benzoate 34 (285 mg, 0.71 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL) gave acid 35 (246 mg, 89%) as a white solid: mp (H2O) 245-248° C.; 1H NMR [(CD3)2SO] δ 13.16 (br s, 1H, CO2H), 8.05 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.93 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.70 (ddd, J=9.0, 2.9, 2.0 Hz, 2H, H-2′, H-6′), 7.13 (ddd, J=9.0, 2.9, 2.0 Hz, 2H, H-3′, H-5′), 4.61 (s, 2H, CH2SO2), 3.84 (s, 3H, OCH3), 2.14 (s, 3H, CH3); MS m/z 388.5 (MH+, 100%). Anal. calcd for C19H17NO6S: C, 58.91; H, 4.42; N, 3.62. Found: C, 58.86; H, 4.22; N, 3.54%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:35])[CH3:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (81 mg, 0.25 mmol), N,N-diisopropyl ethyl amine (195 μL, 1.14 mmol) and isopropylamine (22 μL, 0.25 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated and purification by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) afforded the title compound (60 mg, 71%) as a white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][I:21])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.C(OCC)(=O)C>[C:31]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][I:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COC1C(O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1C(OC(C)=O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (2.08 g). To the solution were added dimethylaminopyridine (0.74 g) and acetic anhydride (0.58 ml). The mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the solvent was purified by means of a silica gel column chromatography (carrier 100 g, developing solvent: ethyl acetate - hexane=1:3) to afford 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol (2.19 g: yield 95%) as a colorless oily product.
Reaction SMILES: C[N:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[N:8]=[CH:7][C:6]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)=[CH:5][C:4]=2[CH2:3]1.[ClH:29]>C(OCC)C>[ClH:29].[CH3:12][C:10]1([CH3:13])[C:9]2[N:8]=[CH:7][C:6]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)=[CH:5][C:4]=2[CH2:3][NH:2][CH2:11]1
Reactant: COc1ccc(C(=O)Nc2cnc3c(c2)CN(C)CC3(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CNCC3(C)C)cc1C(F)(F)F

Procedure:
N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide (172 mg; 0.44 mmol) was suspended in 1,2-dichloromethane (30 ml) and the mixture treated with 1-chloroethyl chlioroformate (62.5 mg: 47 ml; 0.44 mmol). The mixture was heated at reflux and more chlioroformate added until little or no starting material remained. At this point. the volatiles were removed under reduced pressure and the residue dissolved in methanol (30 ml) and heated at reflux for 15 min. The volatiles were removed under reduced pressure and the residue treated with a mixture of 0.88 aqueous ammonia/methanol/dichloromethane (0.5: 4.5:95) and the resulting, beige solid was collected by filtration. The free base (123 mg; 0.32 mmol) was dissolved in methanol (min. vol) and treated with IM hydrogen chloride in diethyl ether (0.32 ml: 0.32 mmol) and the mixture diluted with diethyl ether to turbidity and refrigerated. The title compound was obtained as white powder (130 mg: 71%).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=4[CH3:33])[CH:22]=[C:23]([CH3:24])[C:15]=23)[CH2:10][CH2:9]1)=O)C.Cl.[OH-].[Na+]>O1CCCC1.O.CO>[Cl:32][C:28]1[CH:29]=[C:30]([CH3:31])[C:25]([N:21]2[C:16]3=[N:17][C:18]([CH3:20])=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][CH:8]([CH2:6][OH:5])[CH2:13][CH2:12]4)=[C:15]3[C:23]([CH3:24])=[CH:22]2)=[C:26]([CH3:33])[CH:27]=1
Reactant: CCOC(=O)C1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Cl)cc2C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a suspension of lithium borohydride (4.11 g) in tetrahydrofuran (50 mL) was added a solution of 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) in a mixture of tertrahydrofuran (80 mL) and methanol (7.7 mL) in an ice-cooling bath. The mixture was stirred at room temperature for 2 hours. After cooling with an ice-cooling bath, water was added and the mixture was poured slowly into a 3M HCl aqueous solution. The solution was made to alkaline (pH=8) with 4 M NaOH aqueous solution to give a solid. The solid was collected by filtration and washed with water and diethylether. The solid was recrystallized from a mixture of ethanol and ethyl acetate to give {1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}methanol (9.1 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH3:26]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:26])=[O:24])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Product: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2

Procedure:
Following the procedure in Example 51, 2-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid was coupled with ammonia to give 115. MS(ESI+): 338.1. 1H NMR (400 MHz, DMSO) δ 8.94 (d, J=2.2, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.5, 2.2, 1H), 7.69 (s, 1H), 7.44 (d, J=1.4, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5, 1H), 6.40 (d, J=1.7, 1H), 5.34 (dt, J=13.0, 6.4, 1H), 4.52 (dd, J=11.0, 5.6, 4H), 1.44 (d, J=6.6, 6H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].O>CN(C)C=O>[CH3:1][S:2]([NH:5][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=C(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
Methane sulfonamide (0.476 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), and to the solution was added 60% sodium hydride (0.275 g, 5.00 mmol) and the mixture was stirred in a water bath for 20 minutes. To the reaction mixture was added 3-chloropropiophenone (843 mg, 5.00 mol). The mixture was stirred in a water bath for one hour, and further stirred at room temperature for 15 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 3-(methylsulfonylamino)propiophenone (240 mg, 21%). Step 2: In a manner similar to that in Step 1 of Example 1, 3-(methylsulfonylamino)propiophenone=thiosemicarbazone (219 mg, 45%) was obtained from 3-(methylsulfonylamino)propiophenone (388 mg, 1.71 mmol) prepared above and thiosemicarbazide (156 mg, 1.71 mmol). Step 3: In a manner similar to that in Step 2 of Example 1, Compound 99 (218 mg, 86%) was obtained from 3-(methylsulfonylamino)propiophenone=thiosemicarbazone (200 mg, 0.696 mmol) obtained above, pivaloyl chloride (342 μL, 2.78 mmol) and pyridine (219 μL, 2.78 mmol).
Reaction SMILES: [Ar].N.[Li].[CH2:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([OH:7])/[CH:5]=[CH:6]/[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: C#CCO
Reactant: C=CCCCCBr
Agent: N
Agent: [Ar]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCCCC/C=C/CO
Yield: 77.2 %

Procedure:
100 ml liquid ammonia and a catalytic amount of ferric nitrate (5 mg) are put into a 250 ml three-neck flask which is provided with an agitator, dry-ice condenser, dropping funnel with pressure compensation and with argon/ammonia flushing. 1.88 g (0.268M) lithium is added in portions to this mixture in such a manner that the blue color disappears between the additions. 7.21 g (7.49 ml, 0.129M) propargyl alcohol is added to the reaction mixture in 20 ml dry tetrahydrofuran during 25 minutes and the mixture is allowed to react for 1.5 hours during reflux after the addition. Subsequently, 14.0 g (10.86 ml, 85.8 mM) 1-bromo-5-hexene in 30 ml dry tetrahydrofuran is added over 30 minutes and the mixture is again allowed to react under reflux for 2.5 hours. Then, 2.05 g (0.298M) lithium is added in portions to the reaction mixture and the mixture is allowed to react one more hour. Subsequently, ammonium chloride is added in such an amount that the blue color of the reaction solution disappears and the main amount of the ammonia can evaporate. The reaction mixture is subsequently put in 20 g of ice and the mixture is allowed to warm up overnight to 25° C. The reaction mixture is extracted with ether and dried over magnesium sulfate. After the solvent has been drawn off, 9.3 g (66.4 mM) E-nona-2,8-diene-1-ol is obtained by bulb tube distillation of the residue at 105° C./0.5 mm pressure. This corresponds to a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][P:13]([CH3:17])[O:14]CC)[CH3:11]>[Hg]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[P:13]([CH3:17])(=[O:14])[O:12][CH2:10][CH3:11]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: CCOP(C)OCC
Agent: [Hg]
Product: CCOP(C)(=O)c1cc(Cl)ccc1Cl

Procedure:
Using a high pressure 450 watt mercury lamp, 20 grams of 2,5-dichloroiodobenzene and 30 grams of diethylmethylphosphonite are combined and irradiated for approximately 31/2 hours. After concentration and distillation, a clear oil is obtained, which then solidified. The solid is recrystallized from ethyl ether to give 8.5 g. of white needles having a melting point between 90° and 91° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][CH3:15])=[O:13])[CH:9]=1)([O-])=O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][CH3:15])=[O:13])[CH:9]=1
Reactant: CNC(=O)/C=C/c1cc([N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [S-2]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)/C=C/c1cc(N)ccc1OC
Temperature: 80 °C
Yield: 76.4 %

Procedure:
(E)-3-(5-Nitro-2-methoxy-phenyl)-N-methyl-acrylamide (0.75 g) and sodium sulphide (1.0 g) were combined in 1,4-dioxan/water (1:1, 20 ml) and warmed at 80° C. for 3 h. Solvent was removed at reduced pressure, the residue extracted with 10% methanol/dichloromethane and the extract filtered. The filtrate was evaporated to dryness and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.50 g). 1 H NMR δ: 2.68 (3H, d, J=0.4.8Hz), 3.71 (3H, s), 6.44 (1H, d, J=15.9 Hz), 6.60 (1H, dd, J=2.8 9.2 Hz), 6.73 (1H, d, J=2.8 Hz), 6.78 (1H, d, J=9.2 Hz), 7.57 (1H, d, J=15.9 Hz), 8.00 (1H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]2=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Br[CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:29][C@H:30]3[CH2:31][CH2:32][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:34][CH2:35]3)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]2=[CH:5][N:4]=1
Reactant: CSc1ncc2c(-c3ccccc3)n[nH]c2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncc2c(-c3ccccc3)nn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A microwave tube was charged with 6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.073 g, 0.30 mmol), potassium carbonate (0.14 g, 0.90 mmol), and DMSO (1 mL). The resulting mixture was stirred for 20 min, then was added a solution of tert-butyl trans-4-(bromomethyl)cyclohexylcarbamate (0.10 g, 0.36 mmol) in THF (2 mL). The resulting mixture was heated at 150° C. for 10 min in microwave. The reaction mixture was poured into water and extracted with Et2O (3×). The combined ether layer was dried (Na2SO4) and concentrated. The crude mixture was purified by Isco to provide tert-butyl trans-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.12 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.55-7.44 (t, J=6.8 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 4.37 (bs, 1H), 4.27 (d, J=7.1 Hz, 2H), 3.37 (bs, 1H), 2.61 (s, 3H), 2.09-1.89 (m, 3H), 1.67 (d, J=12.1 Hz, 2H), 1.39 (s, 9H), 1.19 (dd, J=24.4, 10.8 Hz, 2H), 1.04 (ddd, J=25.4, 12.7, 2.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.1, 155.3, 154.8, 152.3, 144.3, 132.2, 129.2, 127.1, 109.3, 79.3, 52.5, 49.7, 37.7, 32.9, 29.6, 28.5, 12.5; MS m/z 454.2 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[CH:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=O.O>CCOCC>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[C:9]([C@@H:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][CH2:17][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:10]=1
Reactant: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reaction time: 96 h
Yield: 20.9 %

Procedure:
A suspension of lithium aluminium hydride (3 g, 0.08 mols) in 350 ml of anhydrous ether is added with 0.5 g of 3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide in portions. The mixture is refluxed while stirring for 4 days. Afterwards, water is carefully added to destroy the lithium aluminium hydride excess, the mixture is acidified to pH 5 with acetic acid, the ether phase is separated and dried over sodium sulfate. The solvent is evaporated to obtain an oil which is purified by flash chromatography (eluent hexane-ethyl acetate 7:3). 0.1 g of tolterodine free base are obtained.